A Cancer Research UK Phase I Trial to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Aurora B Inhibitor GSK1070916A in Patients With Advanced Solid Tumors

RATIONALE: Aurora B/C kinase inhibitor GSK1070916A (GSK1070916A) may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PURPOSE: This phase I trial is studying the side effects and best dose of GSK1070916A in treating patients with advanced solid tumors.

开始日期2010-03-01

申办/合作机构

Cancer Research UK

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2022-11-01·Annals of Translational Medicine

Clinical significance and immune landscape of cuproptosis-related lncRNAs in kidney renal clear cell carcinoma: a bioinformatical analysis

Article

作者: Zhang, Wenzhou ; Song, Wenping ; Wu, Xuan ; Hao, Lidan ; Li, Ding ; Cheng, Cheng

BackgroundKidney renal clear cell carcinoma (KIRC) is considered an immunogenic tumor. Cuproptosis is a newly identified copper-induced regulated cell death that relies on mitochondria respiration. Long noncoding RNAs (lncRNAs) have emerged as significant players in tumorigenesis and metastasis. However, there is a huge knowledge gap on the prognostic role of cuproptosis-related lncRNAs in KIRC. And, the clinical value of them is still unknown. Here, we aimed to develop a cuproptosis-related lncRNA prognostic signature in KIRC.MethodsThe messenger RNA (mRNA)/lncRNA expression profiles and the clinical information including age, gender, tumor stage, grade, and overall survival (OS) were acquired from The Cancer Genome Atlas (TCGA) database. The included KIRC samples were further randomly assigned into training (n=258) or testing (n=257) data sets. We performed Pearson correlation analysis to identify the cuproptosis-related lncRNAs and then constructed the prognostic signature using Cox regression analysis and LASSO algorithm. Subsequently, Kaplan-Meier survival analysis, a nomogram, and receiver operating characteristic (ROC) curve were performed to assess the predictive performance of the signature. Moreover, the immune characteristics and drug sensitivity related to the signature were also explored.ResultsThe signature comprised 7 cuproptosis-related lncRNAs. The patients with a low-risk score had superior OS compared with those with a high-risk score. The survival rates of the high- and low-risk groups were 44.96% and 83.72% (P<0.001). The area under the curve (AUC) value for 1-, 3-, 5-year survival rate reached 0.814, 0.762 and 0.825, respectively. In addition, a nomogram was also generated; the AUC was 0.785 for risk score, higher than that for age (0.593), gender (0.489), grade (0.679), and stage (0.721). The high-risk group had more enriched immune- and tumor-related genes. Patients with low-risk scores were more sensitive to immunotherapy and the small molecular drugs GSK1904529A, tipifarnib, BX-912, FR-180204, and GSK1070916. Meanwhile, the high-risk group tended to be more sensitive to pyrimethamine, MS-275, and CGP-60474.ConclusionsCollectively, we constructed a cuproptosis-related lncRNA prognostic signature with a higher predictive accuracy compared to multiple clinicopathological parameters, which may provide vital guidance for therapeutic strategies in KIRC. Combination of more prognostic biomarkers may further improve the accuracy.

2022-08-21·Disease Markers

KDELR3 Is a Prognostic Biomarker Related to the Immune Infiltration and Chemoresistance of Anticancer Drugs in Uveal Melanoma

Article

作者: Yan, Shilong ; Yu, Lisha ; Zhang, Jingnan ; Zhang, Juan ; Guan, Jing

Uveal melanoma (UM) is an intraocular malignancy in adults in which approximately 50% of patients develop metastatic diseases and have a poor clinical outcome. Immunotherapies are quickly becoming a need, and recent research has produced some amazing achievements in this area. In the current investigation, an attempt was made to evaluate the prognostic usefulness of KDELR3 in UM, particularly its connection with tumor-infiltrating lymphocytes (TILs). The expression patterns of mRNAs and related clinical data of 80 UM patients were obtained from The Cancer Genome Atlas (TCGA). By using RT-PCR, we were able to investigate whether or not UM cells and D78 cells expressed KDELR3. The Kaplan-Meier approach, as well as univariate and multivariate tests, was utilized in order to investigate the potential predictive significance of KDELR3 expression. The associations between KDELR3 and TILs and immunological checkpoints were analyzed in order to evaluate the effect that KDELR3 may have on UM immunotherapy. On the basis of the differential expression of KDELR3, a distribution of the half-maximal inhibitory concentration (IC50) of various targeted medicines was observed. In this study, we found that the expression of KDELR3 was distinctly increased in most types of tumors. In addition, KDELR3 was highly expressed in UM cells. Moreover, patients with high KDELR3 expression exhibited a shorter overall survival and disease-free survival than those with low KDELR3 expression. Multivariate analyses confirmed that KDELR3 expression was an independent prognostic factor for overall survival and disease-free survival in patients with UM. Furthermore, KDELR3 expression was demonstrated to be positively correlated with macrophage M1, T cell CD8, T cell follicular helper, dendritic cell resting, and T cell CD4 memory activated. Meanwhile, the expression of KDELR3 was related to several immune checkpoints. The IC50 of AP-24534, BHG712, bleomycin, camptothecin, cisplatin, cytarabine, GSK1070916, and tipifarnib was higher in the KDELR3 high-expression group. In conclusion, KDELR3 may be applied as a potential diagnostic and prognostic biomarker for UM patients.

2021-06-01·Journal of Assisted Reproduction and Genetics3区 · 医学

Purging human ovarian cortex of contaminating leukaemic cells by targeting the mitotic catastrophe signalling pathway

3区 · 医学

Article

作者: van der Reijden, Bert ; van Leersum, Julia ; Peek, Ronald ; Mulder, Callista ; Koorenhof-Scheele, Thessa ; Beerendonk, Catharina ; van Mello, Norah ; Braat, Didi ; Eijkenboom, Lotte

AbstractPurposeIs it possible to eliminate metastasised chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) cells from ovarian cortex fragments by inhibition of Aurora B/C kinases (AURKB/C) without compromising ovarian tissue or follicles?MethodsHuman ovarian cortex tissue with experimentally induced tumour foci of CML, AML and primary cells of AML patients were exposed to a 24h treatment with 1 μM GSK1070916, an AURKB/C inhibitor, to eliminate malignant cells by invoking mitotic catastrophe. After treatment, the inhibitor was removed, followed by an additional culture period of 6 days to allow any remaining tumour cells to form new foci. Ovarian tissue integrity after treatment was analysed by four different assays. Appropriate controls were included in all experiments.ResultsFoci of metastasised CML and AML cells in ovarian cortex tissue were severely affected by a 24h ex vivo treatment with an AURKB/C inhibitor, leading to the formation of multi-nuclear syncytia and large-scale apoptosis. Ovarian tissue morphology and viability was not compromised by the treatment, as no significant difference was observed regarding the percentage of morphologically normal follicles, follicular viability, glucose uptake or in vitro growth of small follicles between ovarian cortex treated with 1 μM GSK1070916 and the control.ConclusionPurging of CML/AML metastases in ovarian cortex is possible by targeting the Mitotic Catastrophe Signalling Pathway using GSK1070916 without affecting the ovarian tissue. This provides a therapeutic strategy to prevent reintroduction of leukaemia and enhances safety of autotransplantation in leukaemia patients currently considered at high risk for ovarian involvement.

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适应症	最高研发状态	国家/地区	公司	日期
肿瘤	临床2期	-	GSK Plc	-
卵巢癌	临床2期	美国	-	-
非小细胞肺癌	临床前	美国	Nemucore Medical Innovations, Inc.	2019-07-14
费城染色体阳性慢性粒细胞白血病	临床前	美国	Nemucore Medical Innovations, Inc.	2019-06-17
乳腺癌	临床前	美国	Nemucore Medical Innovations, Inc.	2019-05-31
实体瘤	临床前	英国	Cancer Research UK	2015-11-27
急性髓性白血病	药物发现	美国	Nemucore Medical Innovations, Inc.	2019-06-03

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01118611 (ASCO2013)	临床1期	实体瘤 \| HR阳性/HER2低表达实体瘤	38	GSK1070916A	(衊窪夢壓範艱製鏇製淵) = 憲廠夢蓋窪簾鏇膚廠願廠範簾獵憲餘鹹選廠獵 (艱獵構淵衊顧遞鹹餘糧 )	-	2013-05-20